"Urgent Need to Treat Atherosclerotic Cardiovascular Disease Risk Earlier, More Intensively, and with Greater Precision"

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Eddy Edson

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Relationship to Diabetes
Type 2

For LDL, the lower the better, the earlier the better. It's the emerging expert consensus, no matter what the Internet or your GP believe.

There has been compelling and convincing justification for some time that an approach that includes keeping plasma atherogenic lipoproteins low from early in life will greatly reduce risk for ASCVD.
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Humans were never meant to harbor the low-density lipoprotein cholesterol (LDL-C) levels that are now commonplace. ...The fact that animals, non-human primates, and humans who maintain low cholesterol levels from early in life [66] have very little atherosclerosis all suggest that a ‘normal’ non-atherogenic LDL-C level is 20-40 mg/dl [ie about 0.5 - 1.0 mmol/L]. That is of course difficult to achieve in a modern society and, as described herein, is not necessary for most people.
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Based on the log-linear relationship of LDL-C to the hazard ratio for an acute ASCVD event, the LDL-C level where there is no excess risk occurs is approximately 38 mg/dL or 1 mmol/L [67] (Figure 1). This value is consistent with the LDL-C levels observed among hunter-gatherer populations [68,69] In the Framingham Study, the average LDL-C of a man presenting with an Acute Coronary Syndrome (ACS) is approximately 150 mg/dL [70] [about 4 mmol/L] In the Cooper Center Longitudinal Study, even when LDL-C at baseline was < 100 mg/dL [about 2.5 mmol/L], there was a continuous rise in risk for Coronary Heart Disease (CHD) mortality over a mean follow-up time of 26.5 yrs [71] [72] Hence, it is crucial that exposure to atherogenic lipoproteins be dramatically reduced early and over the long-term.

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Atherosclerosis begins in earliest childhood, sometimes even during gestation, presenting as yellow streaks in arterial walls [98], [99], [100], [101], [102]. It is a chronic disease: absent intervention, it slowly progresses throughout life, unevenly, sometimes rapidly [16], but inevitably worsening over time [18,[103], [104], [105], [106], [107], [108]] ... Previously believed to just be part of normal aging, atherosclerosis is actually a pediatric disease that progresses into adulthood [111], [112], [113], [114], [115]. Advanced disease recognized in very young people was observed in young men killed in Korea and Vietnam, as well as victims of trauma as young as 20-25 years of age. [116] Those fatty streak lesions in early childhood are usually the sites of more advanced lesions later in life [117]. ...Childhood risk factors have been shown to predict future clinical atherosclerotic disease by midlife [118].

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Mammals, primates, those living indigenous lives away from ‘modern civilization’ [66], and those with mutations that cause extremely low LDL-C from birth [121] develop little or no significant atherosclerosis [122] The fact that animals, non-human primates, and humans who maintain low cholesterol levels from early in life [66] have very little atherosclerosis all support the conclusion that a ‘normal’ non-atherogenic LDL-C level is below 38 mg/dl [1.0 mmol/L], as noted previously. Other than those with genetically low LDL, what those with little or no atherosclerosis have in common from birth are: [1] low intake of saturated fats, salt, and sugars and other refined carbohydrates, [2] primarily plant-based diets, [3] absence of harmful substance abuse and less polluted environments, and [4] physically active, non-sedentary lives.

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Even when LDL-C is extremely low, there is no impairment of cellular cholesterol production and utilization within the brain because the brain produces its own pool of cholesterol [130], as do all cells in the body. No tissues depend on cholesterol transfer from LDL-C


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While apolipoproteins play the dual role of distributing triglyceride and cholesterol to systemic tissues, their primary role is to facilitate excretion of cholesterol from the bloodstream and the body. [132] Atherosclerosis occurs when those mechanisms are inadequate and lead to excess circulating cholesterol that is deposited in the intimal space of medium to large arteries by transcytosis of LDL particles and atherogenic apo B remnants [18,133].

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Based on the preponderance of evidence, it seems best to set LDL-C goals below 40 mg/dl (1 mmol/dl), or even lower for even higher risk. This is also consistent with current recommendations from the European Society of Cardiology/European Atherosclerosis Society guidelines for the management of dyslipidemia [156] However, that would likely be challenging to achieve widely, but as will be shown in this review, in those with no enhancing risk factors, keeping LDL-C below at most 85 mg/dl [2.2 mmol/L] from birth throughout life would likely delay onset of complications until age 100. This has been derived from experience with those with a heterozygous deficiency in PCSK9. For those with additional risk factors or more advanced atherosclerosis, keeping LDL-C below 38 mg/dl [1.0 mmol/L] (depending on severity) would also likely maintain good health until very late in life.

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Many studies have confirmed that the lower the LDL-C, the lower the risk and the fewer complications of atherosclerosis, with no evidence of any clinically significant harm no matter how low the LDL-C level
 
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Interesting stuff Eddy. Do you know if LDL and LDL-C in this study is actually being measured? Or is it based on the Friedewald Formula estimations that we usually get for LDL?

It seems there are a few newer options for LDL-C estimation, but I’m not sure how widespread their adoption is, or how you know which was used in your own numbers.

 
Interesting stuff Eddy. Do you know if LDL and LDL-C in this study is actually being measured? Or is it based on the Friedewald Formula estimations that we usually get for LDL?

It seems there are a few newer options for LDL-C estimation, but I’m not sure how widespread their adoption is, or how you know which was used in your own numbers.

The paper looks at lots of different studies so I suppose might represent different methods - but I would guess mainly Fredewald based.

I think most experts these days would probably concur with the general view of expert bodies that apoB particle count is actually the real measure of atherosclerosis risk. Each atherosclerotic particle has an apoB particle, the thing which actually causes the damage.

LDL-C is a rough proxy for LDL-P, the LDL particle count, which in turn is a rough proxy for apoB count. But the association becomes sketchier in the case eg of metabolic syndrome and T2D, in which LDL particles tend to be smaller, so more LDL-P for the same LDL-C, and so more apoB. (It's a myth that somehow small, dense LDL particles are worse than big, fluffly ones: they're all equally bad, it's just that for a given LDL-C there will be more apoB if your LDL particles are smaller.)

Non-HDL-C is a better proxy, which the reason you see it embedded in the NICE and NHS guidelines. (HDL/total chol ratios these days are seen as not very useful: for example, increasing HDL has little or no clinical impact, if LDL and trigs remain the same; it is incorrect to view HDL as actively "good" cholesterol; it's mainly just a bystander.)

Directly measuring apoB counts would be best & is not difficult, apparently. Most seem to expect it to become part of the clinical standard, but these changes, no matter however well supported, seem to happen unnecessarily slowly so who knows when.

And you have the obvious issue that most of the research historically has been conducted in terms of LDL-C, so changing metrics may obscure continuity and comparability.
 
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All those proxies, conversions, estimates and (competing/changing) ‘the thing that actually really matters’ are pretty unhelpful to me. The sooner they start actually measuring the thing that matters, the easier I’ll find it!
 
The sooner they start actually measuring the thing that matters, the easier I’ll find it!
It's just a shame that the thing we really want to measure is deaths (or maybe less fatal CV events) and measuring those in humans (outside observational studies) takes a while. I fear we're stuck with proxy measures for trialing many interventions.
 
All those proxies, conversions, estimates and (competing/changing) ‘the thing that actually really matters’ are pretty unhelpful to me. The sooner they start actually measuring the thing that matters, the easier I’ll find it!
I guess you could pay for an apoB test: https://privatebloodtests.co.uk/products/private-blood-test-for-apolipoprotein-b-in-blood

I sometimes think of working out how to do that here or trying to strong-arm my doc into prescribing one, but really just out of nerdiness. LDL-C and non-HDL-C are not bad metrics and the ideally low-as-possible/long-as-possible message is the same.

Also the steps for reducing risk are the same: reduce satfats, reduce refined carbs, increase fibre, exercise, take statin (or better, PCSK9 inhibitors if/when they become affordable).
 
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